Freeze-drying, also known as lyophilization, is a dehydration process that enables removal by sublimation of water and/or solvents from a substance, such as food, pharmaceutical or biological products. Typically the freeze-drying process is used to preserve a perishable product since the greatly reduced water content that results inhibits the action of microorganisms and enzymes that would normally spoil or degrade the product. Furthermore, the process makes the product more convenient for transport. Freeze-dried products can be sealed in containers to prevent the reabsorption of moisture and can be easily rehydrated or reconstituted by addition of removed water and/or solvents. In this way the product may be stored at room temperature without refrigeration, and be protected against spoilage for many years.
Since freeze-drying is a low temperature process in which the temperature of product does not exceed typically 30° C. during the operating phases, it causes less damage or degradation to the product than other dehydration processes using higher temperatures. Freeze-drying does not usually cause significant shrinkage or toughening of the product being dried. Freeze-dried products can be rehydrated much more quickly and easily because of the porous structure created during the sublimation of ice.
In the pharmaceutical field, freeze-drying process is widely used in the production of pharmaceuticals, mainly for parenteral and oral administration, also because freeze-drying process can be carried out in sterile conditions.
A known freeze-dryer apparatus for performing a freeze-drying process usually comprises a drying chamber and a condenser chamber interconnected by a duct that is provided with a valve that allows isolating the drying chamber when required during the process.
FIG. 1 shows the drying chamber which comprises a plurality of temperature-controlled shelves arranged for receiving containers of product to the dried. The condenser chamber includes condenser plates or coils having surfaces maintained at very low temperature, e.g. −50° C., by means of a refrigerant of freezing device. The condenser chamber is also connected to one or more vacuum pumps so as to achieve high vacuum values inside both chambers.
Freeze-drying process typically comprises three phases: a freezing phase, a primary drying phase and a secondary drying phase.
During the freezing phase the shelf temperature is reduced up to typically −30/−40° C. in order to convert into ice most of the water and/or solvents contained in the product.
In the primary drying phase the shelf temperature is increased, while the pressure inside the drying chamber is lowered below 1-5 mbar so as to allow the frozen water and/or solvents in the product to sublime directly from solid phase to gas phase. The application of high vacuum makes possible the water sublimation at low temperatures.
Heat is supplied to the product and the vapour generated by sublimation of frozen water and/or solvents is removed from the drying chamber by means of condenser plates or coils of condenser chamber wherein the vapour can be re-solidified.
Secondary drying phase is provided for removing by desorption the residual moisture of the product, namely the amount of unfrozen water and/or solvents that cannot be removed during primary drying when sublimation of ice takes place. During this phase the shelf temperature is further increased up to a maximum of 30-60° C. to heat the product, while the pressure inside the drying chamber is set typically below 0.1 mbar.
At the end of secondary drying phase the product is sufficiently dried with residual moisture content typically of 1-3%.
Secondary drying has to be carefully monitored in order to point out when the drying process is completed, i.e. when the desired amount of residual moisture in the product has been achieved.
There are known methods for monitoring secondary drying phase.
According to a known method the residual moisture of the product can be determined by extracting samples from the freeze-dryer without interrupting the freeze-drying (e.g. using a “sample thief”) and measuring off-line their moisture content by means of Karl Fischer titration, thermal gravimetric analysis, or near Infra-Red spectroscopy.
U.S. Pat. No. 6,971,187 proposes another method wherein the estimation of the drying rate of the product during the secondary drying is obtained by performing a Pressure Rise Test (PRT).
During a PRT the drying chamber is isolated from the condenser chamber by closing the valve positioned in the duct connecting the two chambers. As the heating is not stopped, the ice sublimation continues, thus increasing in the drying chamber the pressure that can be measured.
Given the curve of pressure vs. time, the slope at the beginning of this curve allows estimating the flow rate of water and/or solvent from the product by the equation:
                                                        d              ⁢                                                          ⁢              P                                      d              ⁢                                                          ⁢              t                                ⁢                      |                          t              =                              t                0                                                    =                              RT            V                    ⁢                      j                          w              ,              n                                                          (                  eq          .                                          ⁢          1                )            
where:
P: measured pressure, [Pa]
t: time, [s]
t0: time instant at the beginning of the PRT, [s]
R: gas constant [8.314 J mol−1 K−1]
T: temperature of the vapour, [K]
V: (free) volume of the chamber, [m3]
jw,n: flow rate of water and/or solvent from the product, [mol s−1]
Thus, the mass flow of water and/or solvent can be calculated:
                              j                      w            ,            m                          =                                            M              w                        ⁢                          V              RT                        ⁢                                          d                ⁢                                                                  ⁢                P                                            d                ⁢                                                                  ⁢                t                                              ⁢                      |                          t              =                              t                0                                                                        (                  eq          .                                          ⁢          2                )            
where:
jw,m: mass flow of water and/or solvent from the product, [kg s−1]
Mw: molecular weight of water and/or solvent, [kg mol−1]
From this value, the loss in water and/or solvent during the measurement period elapsed between two consecutive PRTs can be estimated by:Δwm,j=jw,m,j−1Δtj  (eq. 3)
where:                tj=tj−tj−1 time elapsed between j-th PRT and (j−1)th PRT, [s]        wm,j: loss in water during the time interval tj, [kg]        
jw,m,j−1: mass flow of water and/or solvent from the product calculated from the (j−1)-th PRT, [kg s−1].
The total amount of water and/or solvent removed between a reference time t0 (e.g. the start of the secondary drying) and any given time of interest tj is simply the summation of all the wm,j occurring in the various intervals between PRTs. Exploiting one independent experimental value for detecting the residual water content at a reference time, e.g. at the end of primary drying, the real time actual moisture content vs. time can be calculated. This requires extracting a sample from the drying chamber or using expensive sensors (e.g. NIR-based sensors) to get this value in-line.
Given this experimental value, some empirical or common sense indications are given to calculate the “optimal” temperature to minimize the time required to complete the secondary drying.
A disadvantage of the above known methods consists in that they require extracting samples from the drying chamber and using expensive sensors for measuring the experimental values of residual water and/or solvent. Samples extraction is an invasive operation that perturbs the freeze-drying process and thus it is not suitable in sterile and/or aseptic processes and/or when automatic loading/unloading of the containers is used. Furthermore, sample extraction is time consuming and requires skilled operators.
Another disadvantage of the method disclosed in U.S. Pat. No. 6,971,187 is that the empirical and common sense indications used for calculating the “optimal” temperature do not allow to optimize the process.
A different approach is disclosed in U.S. Pat. No. 6,176,121 wherein using two successive measurements of desorption rate (DR), i.e. the mass flow rate of the water and/or solvent vapour due to desorption, calculated from jw,m, it is possible to extrapolate the point in time at which a given small value of DR is obtained. In order to do this, the valve placed between the drying chamber and the condenser chamber should be regularly closed for a certain time and the pressure rise curve (PRC), caused by the desorbing water vapour, has to be acquired. Thus, the mass of desorbed water and/or solvent over the time, or rather the desorption rate, can be calculated from the initial slope of the PRC as follows:
                              DR          exp                =                                            VM              w                        RT                    ⁢                                    (                                                d                  ⁢                                                                          ⁢                  P                                                  d                  ⁢                                                                          ⁢                  t                                            )                                      t              =                              t                0                                              ⁢                      100                          m              dried                                                          (                  eq          .                                          ⁢          4                )            
where:
mdried: mass of the dried product, [kg]
DRexp: experimental desorption rate, [% of water and/or solvent over dried product s−1]
A disadvantage of this method consists in that, due to the very simplified approach, it is shown to fail in correspondence of the end of secondary drying. Moreover, it does not allow to estimate the absolute residual moisture, but only the difference with respect to the equilibrium moisture, which depends on the operating conditions (shelf temperature and drying chamber pressure), and therefore no target about this value can be set.
An object of the invention is to improve the methods for monitoring a freeze-drying process in a freeze-dryer, particularly for monitoring a secondary drying phase of said freeze-drying process.
A further object is to provide a method for calculating process parameters, such as residual moisture content and/or desorption rate of a dried product, that is non-invasive and not-perturbing the freeze-drying process and thus is suitable for being used in sterile and/or aseptic processes and/or when automatic loading/unloading of the containers is used.
Another object is to provide a method capable to precisely estimate initial conditions and kinetic constants of a kinetic model of the drying process, suitable for calculating the process parameters.
Still another object is to provide a method for estimating in a reliable and precise way a residual moisture concentration and/or desorption rate of the dried product during secondary drying phase and a time required for terminating said secondary drying phase.
Another further object is to provide a method wherein estimation of process parameters is progressively improved and refined during progress of secondary drying phase, said estimation being nevertheless good with respect to known methods even at the beginning of secondary drying phase.